Primary CNS Tumors Research Articles

Pharmacokinetics of bendamustine in the central nervous system: chemoinformatic screening followed by validation in a murine model

Bendamustine is a novel bifunctional chemotherapeutic agent with activity against multiple cancers. There has been no definitive data on its capacity to penetrate the central nervous system. Our chemoinformatic screening predicted excellent CNS penetration, which was validated by in vivo pharmacokinetic analysis in mice. Bendamustine has 35% CNS penetration in our mouse model. Bendamustine should be further evaluated for use in treatment of primary and secondary CNS tumors.

Incidental findings of mass lesions on neuroimages in children

Increasing use of neuroimaging in children has led to more incidental findings of CNS mass lesions, the management of which is uncertain. The authors' aims in this study are to describe these mass lesions and their evolution, as well as to discuss the management options and determine the prevalence of incidental CNS mass lesions at their pediatric clinic. A retrospective study was undertaken in children with primary CNS tumors who were younger than 18 years old and were admitted to the University Children's Hospital of Zurich, Switzerland, between January 1995 and December 2010. In 19 (5.7%) of 335 patients with newly diagnosed CNS tumors, the diagnosis of a CNS mass lesion was an incidental finding. Reasons for obtaining neuroimages in these 19 patients were head trauma (in 6 patients); research protocols (in 3); nasal/orbital malformations (in 2); endocrinological and psychiatric evaluations (in 2); and vertebral bone anomaly without neurological signs, absence seizures, congenital ataxia, recurrent vomiting, developmental delay, and "check-up" at the explicit request of the parents (in 1 patient each). Seven patients underwent immediate surgery for low-grade glioma (4 patients) and craniopharyngioma, ependymoma, and choroid plexus papilloma (1 patient each); and 12 were treated conservatively or were observed. Ten of 12 conservatively treated patients remained stable (median follow-up time 1.8 years) and the other 2 underwent delayed surgery because of tumor progression (medulloblastoma in one patient and fibrillary astrocytoma in the other). Clinicians are increasingly challenged by the discovery of incidental CNS mass lesions. A subgroup of such lesions (with typical imaging patterns such as tectal glioma and dysembryoplastic neuroepithelial tumor) can be monitored conservatively, clinically, and radiographically. Future prospective studies are needed to define optimal management strategies based on larger collections of natural histories, as well as to assess the true prevalence of incidental CNS mass lesions.

Expression of Eukaryoteic Initiation Factor 4E in the Children with Medulloblastoma

Medulloblastoma, a neuroectodermal tumor arising in the cerebellum, is the most common malignant brain tumor in children, accounting for 10-20% of primary CNS neoplasms and approximately 40% of all posterior fossa tumors. Medulloblastoma is heterogeneous, being characterized by molecular subgroups that demonstrate distinct gene expression profiles. The cellular and molecular events involved in the progression of medulloblastoma are largely unknown. Increased protein synthesis is necessary for the transition of cells from quiescence to proliferation. Translational control is critical for the proper regulation of the cell cycle, tissue induction and growth. Eukaryotic initiation factor 4E (eIF4E), an important regulator of translation, plays critical roles in neo-plastic transformation and tumor progression. The aim of this study is to determine the pattern of eIF4E expression in the children with medulloblastoma. Tumor and normal adjacent tissue samples (as controls) were obtained from 28 children with medulloblastoma. eIF4E expression were determined by using Western blot analysis. In the medulloblastoma tissues, eIF4E level was elevated by a mean of 8.22 ± 1.41-fold when compared to normal adjacent tissues. eIF4E expression was higher in tumors compared to control tissues. The results from this study support the hypothesis that the overexpression of eIF4E can be involved in tumorigenesis and a possible role of eIF4E as a prognostic factor in medulloblastoma.

Treatment of high-grade glioma in children and adolescents.

Pediatric high-grade gliomas (HGGs)--including glioblastoma multiforme, anaplastic astrocytoma, and diffuse intrinsic pontine glioma--are difficult to treat and are associated with an extremely poor prognosis. There are no effective chemotherapeutic regimens for the treatment of pediatric HGG, but many new treatment options are in active investigation. There are crucial molecular differences between adult and pediatric HGG such that results from adult clinical trials cannot simply be extrapolated to children. Molecular markers overexpressed in pediatric HGG include PDGFRα and P53. Amplification of EGFR is observed, but to a lesser degree than in adult HGG. Potential molecular targets and new therapies in development for pediatric HGG are described in this review. Research into bevacizumab in pediatric HGG indicates that its activity is less than that observed in adult HGG. Similarly, tipifarnib was found to have minimal activity in pediatric HGG, whereas gefitinib has shown greater effects. After promising phase I findings in children with primary CNS tumors, the integrin inhibitor cilengitide is being investigated in a phase II trial in pediatric HGG. Studies are also ongoing in pediatric HGG with 2 EGFR inhibitors: cetuximab and nimotuzumab. Other novel treatment modalities under investigation include dendritic cell-based vaccinations, boron neutron capture therapy, and telomerase inhibition. While the results of these trials are keenly awaited, the current belief is that multimodal therapy holds the greatest promise. Research efforts should be directed toward building multitherapeutic regimens that are well tolerated and that offer the greatest antitumor activity in the setting of pediatric HGG.

Proteomic identification of glutamine synthetase as a differential marker for oligodendrogliomas and astrocytomas

Astrocytomas and oligodendrogliomas are primary CNS tumors that remain a challenge to differentiate histologically because of their morphological variability and because there is a lack of reliable differential diagnostic markers. To identify proteins that are differentially expressed between astrocytomas and oligodendrogliomas, the authors analyzed the proteomic expression patterns and identified uniquely expressed proteins in these neoplasms. Proteomes of astrocytomas and oligodendrogliomas were analyzed using 2D gel electrophoresis and subsequent computerized gel analysis to detect differentially expressed proteins. The proteins were identified using high-performance liquid chromatography accompanied by tandem mass spectrometry. To determine the role of the differentially expressed proteins in astrocytes, undifferentiated glial cell cultures were treated with dibutyryl-cyclic adenosine monophosphate (cAMP). Two-dimensional gel electrophoresis revealed that glutamine synthetase was differentially expressed in astrocytomas and oligodendrogliomas. Western blot and immunohistochemical analyses confirmed the increased expression of glutamine synthetase in astrocytomas compared with oligodendrogliomas. Whereas glutamine synthetase expression was demonstrated across all grades of astrocytomas (Grade II-IV [15 tumors]) and oligoastrocytomas (4 tumors), it was expressed in only 1 oligodendroglioma (6% [16 tumors]). Treatment of undifferentiated glial cell cultures with dibutyryl-cAMP resulted in astrocyte differentiation that was associated with increased levels of glial fibrillary acidic protein and glutamine synthetase. These data indicate that glutamine synthetase expression can be used to distinguish astrocytic from oligodendroglial tumors and may play a role in the pathogenesis of astrocytomas.

Photodynamic therapy (PDT) in the multidisciplinary treatment of brain tumors: A feasibility study.

2094 Background: Usual treatment of brain tumors includes surgery, radiotherapy and chemotherapy, but the general prognosis is bad, with local relapse as the main cause of death. PDT is a local anticancer treatment that has showed promising results in other tumors (GI, H&N, etc) and can be administered in addition to the classical modalities. Methods: Patients (pts) diagnosed of primary, relapsed or metastatic (mets) brain tumors received an endovenous photosensitizer agent (Photofrin or Foscan). After a 2-4 days period, the tumor was removed. The residual cavity was exposed to a special laser during a predetermined time, in order to achieve the optimal activation of the photosensitizer that, once activated, kills the residual tumor cells. Complementary treatment with radio and chemotherapy was also administered after surgical recovery. Results: From December 2000 to January 2011, 51 pts (34 M/ 17 F; age 13-73, median 51) were treated with a total of 61 procedures (22 Photofrin, 39 Foscan). Diagnoses were glioblastoma (20), gliosarcoma (1), anaplastic astrocitoma (9), grade 2 astrocitoma (7), oligodendroglioma (6, 2 anaplastic), malignant meningioma (1), lung ca. mets (4), breast ca. mets (3). 18/44 primary CNS tumor pts had PDT at the initial resection procedure and 32 procedures were performed at the time of relapse. In 10 cases a second procedure was performed after relapse. Toxicity: 2 pts with thalamic gliomas died in the first 24 h; 6 pts presented postoperative neurological alterations, recovering in 3 to 17 days, and 4 pts presented cutaneous ulcerations related to the PDT, one of them requiring plastic surgery. Median OS of the treated primary brain tumors was 13 m (0-120+) and 8 pts are alive at 1+, 71+, 92+, 93+, 96+, 98+, 104+, and 120+ m (1 GBM, 1 AA, 3 grade 2 A, 3 OD). Conclusions: PDT can be safely used in the multidisciplinary treatment of brain tumors. In this group of heavily treated pts, it clearly benefits some of them, showing an improvement in OS over expected from historical data. Further studies are warranted.

Phase I Trial of Lenalidomide in Pediatric Patients With Recurrent, Refractory, or Progressive Primary CNS Tumors: Pediatric Brain Tumor Consortium Study PBTC-018

A phase I trial of lenalidomide was performed in children with recurrent, refractory, or progressive primary CNS tumors to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile and pharmacokinetics. Lenalidomide was administered by mouth daily for 21 days, repeated every 28 days. The starting dose was 15 mg/m(2)/d orally, and the dose was escalated according to a modified continuous reassessment method. Correlative studies included pharmacokinetics obtained from consenting patients on course 1, day 1, and at steady-state (between days 7 and 21). Fifty-one patients (median age, 10 years; range, 2 to 21 years) were enrolled. Forty-four patients were evaluable for dose finding, and 49 patients were evaluable for toxicity. The primary toxicity was myelosuppression, but the MTD was not defined because doses up to 116 mg/m(2)/d were well-tolerated during the dose-finding period. Two objective responses were observed (one in thalamic juvenile pilocytic astrocytoma and one in optic pathway glioma) at dose levels of 88 and 116 mg/m(2)/d. Twenty-three patients, representing all dose levels, received ≥ six cycles of therapy. Pharmacokinetic analysis demonstrated that the lenalidomide area under the concentration-time curve from 0 to 24 hours and maximum plasma concentration increased with dosage over the range studied. Lenalidomide was tolerable in children with CNS tumors at doses of 116 mg/m(2)/d during the initial dose-finding period. The primary toxicity is myelosuppression. Antitumor activity, defined by both objective responses and long-term stable disease, was observed, primarily in patients with low-grade gliomas.

420 Fetal Growth, Preterm Birth, Neonatal Stress and Risk for Cns Tumors in Children: A Nordic Populationand Register-Based Case- Control Study

We investigated the association between indicators of fetal growth and neonatal stress and CNS tumours diagnosed in the Denmark, Sweden, Norway and Finland in 1985-2006, using data from national cancer registries and medical birth registries. We included 3,443 children with primary CNS tumours and 16169 individually matched controls drawn randomly from the national population registries. We observed a U-shaped relation between risk for CNS tumors and birthweight, at >4.5 kg (OR 1.27; 95% CI, 1.03-1.55) and 38 cm (1.80; 95% CI, 1.18- 2.74), 5-minute Apgar score < 7 (1.44;95% CI, 0.98-2.12), and breech presentation (1.33; 95% CI, 1.04-1.69). The observed associations varied little by histologic subgroup. This study provides evidence that several intrauterine and neonatal factors are associated with higher risk of CNS tumours, indicating an early onset or, alternatively, potentially harmful exposures in the neonatal period that might be preventable.

Magnetohyperthermia for treatment of gliomas: experimental and clinical studies.

Gliomas comprise a group of heterogeneous primary tumors of the central nervous system that originate from glial cells. Malignant gliomas account for the majority of primary malignant CNS tumors and are associated with high morbidity and mortality. Glioblastoma is the most frequent malignant glioma, and despite recent advances in diagnosis and new treatment options, its prognosis remains dismal. New opportunities for the development of effective therapies for malignant gliomas are urgently needed. Magnetohyperthermia consists of heat generation in the region of the tumor through the application of magnetic nanoparticles subjected to an alternating magnetic field and has shown positive results in both preclinical and clinical assays. The aim of this review was to assess the relevance of hyperthermia induced by magnetic nanoparticles in treating gliomas and to describe possible variations of the technique and its implication in the effectiveness of treatment. An electronic search in the literature of articles published from January 1990 to November 2009 was performed, in databases ISI Web of Science and PubMed, and after screening according to the inclusion criteria, 11 articles were selected. Animal models showed that magnetohyperthermia was effective in promoting tumor cell death and reducing tumor mass or increasing survival of the animals. One clinical study demonstrated that magnetohyperthermia could be applied safely and with few adverse effects. Some studies suggested that mechanisms of cell death, such as apoptosis, necrosis, and antitumor immune response were triggered by magnetohyperthermia. Based on these data, it was concluded that the technique proved to be effective in most experiments, and improvement of the nanocomposites, as well as of the alternating magnetic field equipment, can contribute towards establishing magnetohyperthermia as a promising tool to treat malignant gliomas.

Tumor grade-related NDRG2 gene expression in primary and recurrent intracranial meningiomas

Approximately 30% of all primary CNS tumors are meningiomas. Depending on histological type, meningiomas can recur as follows: benign--with five-year recurrence of 5%, atypical--recurrence approximately 40%, and anaplastic with recurrence of 50-80%. In an attempt to understand the molecular mechanism of meningioma recurrence we investigated the N-Myc downstream-regulated gene 2 (NDRG2), which has recently been described as important in suppressing cellular carcinogenesis in different types of cancer. The objective of the study was to investigate NDRG2 gene expression at the mRNA level in primary and recurrent meningiomas as a potential marker of tumor aggressiveness, malignancy, and recurrence. Primary and recurrent meningiomas of WHO grades I, II, and III from 35 patients operated on between 2005 and 2008 year at the Department of Neurosurgery of Kaunas Medical University Hospital (Lithuania) were studied. Using the qRT-PCR method we measured NDRG2 gene expression at the mRNA level in primary (n = 24) and recurrent (n = 11) meningiomas. Statistically significant differences in NDRG2 gene expression level were observed between primary and recurrent meningioma groups (P < 0.05) and between benign (WHO grade I) and atypical (WHO grade II) meningiomas (P < 0.05). No statistically significant differences were observed (P > 0.05) among histological subtypes of benign (WHO grade I) meningiomas: fibrous, meningothelial, and transitional. In accordance with our results, reduction of NDRG2 gene expression at the mRNA level could help to explain malignant progression and predisposition to recurrence in meningiomas.

Clinical presentation, histology, and treatment in 430 patients with primary tumors of the spinal cord, spinal meninges, or cauda equina

OBJECT Patients having a primary tumor of the spinal cord, spinal meninges or cauda equina, are relatively rare. Neurosurgeons encounter and treat such patients, and need to be aware of their clinical presentation, tumor types, treatment options, and potential complications. The purpose of this paper is to report results from a series of 430 patients with primary intraspinal tumors, taken from a larger cohort of 9661 patients with primary tumors of the CNS. METHODS Extensive information on individuals diagnosed (in the year 2000) as having a primary CNS neoplasm was prospectively collected in a Patient Care Evaluation Study conducted by the Commission on Cancer of the American College of Surgeons. Data from US hospital cancer registries were submitted directly to the National Cancer Database. Intraspinal tumor cases were identified based on ICD-O-2 topography codes C70.1, C72.0, and C72.1. Analyses were performed using SPSS. RESULTS Patients with primary intraspinal tumors represented 4.5% of the CNS tumor group, and had a mean age of 49.3 years. Pain was the most common presenting symptom, while the most common tumor types were meningioma (24.4%), ependymoma (23.7%), and schwannoma (21.2%). Resection, surgical biopsy, or both were performed in 89.3% of cases. Complications were low, but included neurological worsening (2.2%) and infection (1.6%). Radiation therapy and chemotherapy were administered to 20.3% and 5.6% of patients, respectively. CONCLUSIONS Data from this study are suitable for benchmarking, describing prevailing patterns of care, and generating additional hypotheses for future studies.

Intrathecal chemotherapy for treatment of leptomeningeal dissemination of metastatic tumours

Neoplastic meningitis consists of diffuse involvement of the leptomeninges by infiltrating cancer cells, and can be caused by systemic or primary CNS tumours, such as solid cancers or lymphoproliferative malignant disease. Neoplastic meningitis is characterised by multifocal neurological signs and symptoms. Thus, careful neurological examination is needed for diagnosis of secondary diffuse involvement. Survival of patients with neoplastic meningitis is short (3-4 months), although some patients have long-lasting remission. Because most patients with neoplastic meningitis have diffuse systemic disease, treatment is typically palliative. However, more aggressive treatments are available to low-risk patients, which could increase survival. Therefore, identification of low-risk patients is important. Intrathecal chemotherapy is currently the main treatment for patients with neoplastic meningitis, but optimum anticancer chemotherapy is being studied.

Diagnostic and prognostic molecular markers in common adult gliomas

The majority of primary CNS tumors in adults are comprised of gliomas (astrocytomas, oligodendrogliomas and ependymomas). The diagnosis has historically been based on the histologic appearance of these tumors. However, as molecular data have accumulated over the years, there is considerable evidence that the molecular diversity (even within the same diagnostic entity) may account for the heterogeneity of clinical outcomes, such as response to treatment, time to progression and overall survival after diagnosis. These molecular markers are becoming more useful in the field of neuro-oncology. They can assist in diagnosis, provide prognostic information and potentially predict response to therapy. Perhaps the greatest potential for these molecular aberrations is that they may represent therapeutic targets themselves. In this article, we summarize the findings of important, published biomarker studies in adult gliomas and provide an overview of the practical uses of these markers in the clinical setting, as well as the current understanding of molecular gliomagenesis.

Gliosarcoma: A rare primary CNS tumor. Presentation of two cases

Gliosarcoma is a very rare primary mixed tumor in the central nervous system, with a biphasic pattern consisting of glial and malignant mesenchymal elements. Its onset is between the fourth and sixth decade of life, and it has a male/female ratio of 1.8/1. Here we present two cases of Gliosarcoma treated in our department. The monoclonal or biclonal origin of its biphasic nature is still subject to debate; hence the importance of its diagnosis and histogenesis. Standard treatment consists in surgical resection of the tumor followed in some cases by external radiotherapy and chemotherapy.

Reconsidering the lifetime deferral of blood donation by men who have sex with men

Although leptomeningeal spread (LMS) of primary CNS tumors in children has been well documented in the literature, it has rarely been reported in children with low-grade gliomas. Between 1975 and 1985, 6 of 162 children (3.7%) with low-grade gliomas treated at Children9s Hospital of Philadelphia had LMS. LMS was present at diagnosis of the original tumor in one patient, was the first sign of relapse in one patient, occurred simultaneously with local relapse in two patients, and after local relapse in two patients. Pathology of the original tumor was low-grade astrocytoma in five and low-grade oligodendroglioma in one. Primary tumor site was cervical cord in three, chiasm in one, frontal lobe in one, and cerebellum in one. All of the children with LMS had undergone surgical treatment at the time of diagnosis of the primary tumor; four had total resections at some point in their course. Three of the six patients died; three are still alive after treatment with radiation therapy and/or chemotherapy. The longest survival to date has been 3¹/₂ years after diagnosis of LMS. We compared clinical characteristics of these six patients with 131 children with low-grade tumors without dissemination treated at our institution during the same time period. LMS, although relatively infrequent, does occur in children with low-grade gliomas, especially spinal cord tumors. LMS may occur at any time during illness and diagnosis may be difficult unless LMS is suspected. Treatment, at times, results in clinical improvement and considerable disease control.

Randomized phase II study of two cross-over sequences comprising vinorelbine/cyclophosphamide and temozolomide/etoposide in outpatient setting for relapsed or refractory solid tumors in children and young adults.

TPS328 Background: Both vinorelbine (VNR) and temozolomide (TMZ), as well as camptotecin derivatives, are regarded as highly promising developmental cytotoxic drugs against pediatric malignancy, so that FDA designated the both drugs as “exclusivity granted,” reported in ASCO 2003. The purpose of this study is to examine safety and efficacy of VNR/cyclophosphamide (CY) (R1) and TMZ/etoposide (VP) (R2), both of which have reported in one adult phase II trial, respectively, in children and young patients (pts) with refractory solid tumors. We also assess which sequence of the two regimens could improve survival with minimum burden. Methods: Eligibility: Pts aged between 3 and 30 years of age with solid tumors (including primary CNS tumors) refractory or relapsed despite disease-specific standard chemotherapies are eligible. Other pts requirements were as follows: PS (ECOG) 0-2; normal organ function; appropriate interval from prior antitumor therapies; no history of either VNR or TMZ use; obtained written informed consent. The study is approved by the local ethical committees of the participating institutions. Treatment plan: In R1, VNR 25mg/m2 intravenously on day1, day8, and day15 and CY orally 25mg/m2 daily in 28 day-cycle. In R2, TMZ 150 mg/m2 orally day 1 to day 5 and VP 50 mg/m2 orally day1 to day 12 in 28 day-cycle. All pts are treated in outpatient setting. Study design: Multi-center, open-label, cross-over randomized phase II. Pts are randomized to group-A or group-B. In group-A, pt receives R1 until progression and then switches to R2 (1st sequence). Pt in group B receives these regimens in reverse order (2nd sequence). Planned sample size is 22 / group (the probability of correct selection is more than 80% when median survivals are 6 months vs. 8 months and survival times are exponentially distributed). Endpoints: Primary endpoint is overall survival. Secondary endpoints includes progression free survival, time to treatment failure, response rate, adverse events, self- reported QOL with face scale, number of days attending school/workplace, and number of days without hospital visit or stay. No significant financial relationships to disclose.

Clinical manifestation of central nervous system tumor

Tumors of the brain and spinal cord (central nervous system, CNS) are rare when compared with other sites and other diseases that can affect the length of an individual's life. However, about 20,000 new cases of primary CNS tumors are diagnosed in the United States each year, not an insignificant number. The CNS is "locked" inside a rigid and nonexpandable calvarium (except in newborns and young children); therefore, any new growths (primary or secondary) can only grow at the expense of the structures already inside the skull or spinal column. The symptoms and signs or clinical manifestations of CNS tumors depend on the location and the growth rate of these tumors. Symptoms include general nonlocalizing and focal symptoms and signs. General signs, which reflect the increase in intracranial pressure, include drowsiness, confusion, headache, nausea, vomiting, sixth nerve palsy, papilledema, generalized seizures, and cognitive impairment. Focal signs and symptoms reflect the effect of the tumor on specific structures. Special imaging techniques (such as computed tomography, magnetic resonance imaging, and positron emission tomography) are essential for the localization of the lesion and for image-guided brain biopsies. The handling of these tiny biopsies often presents significant diagnostic challenges, especially at the time of frozen section examination.

Cadherin-dependent adhesion of human U373MG glioblastoma cells promotes neurite outgrowth and increases migratory capacity

The current management of primary CNS tumors involves a multimodal approach, incorporating cytoreductive techniques including resection, radiotherapy, and antiproliferative chemotherapeutic agents. Despite these attempts, the majority of patients with a diagnosis of a high-grade glioma have a dismal prognosis, with the leading cause of treatment failure and tumor recurrence attributable to local invasion of adjacent brain parenchyma. The current study examines the capacity of glioma tumor cells to undergo neurite outgrowth and local migration, specifically focusing on the role of the cadherin cell adhesion system. Using a recombinant cadherin ectodomain protein, U373MG human glioblastoma cells were assessed for their ability to adhere and migrate in a cadherin-dependent manner in culture. Adhesion was evaluated via growth assessment and neurite length at 72 hours growth on an immobilized cadherin substrate and compared with other matrix adhesion proteins, such as Type IV collagen and vitronectin. Migratory capacity was measured via modified transwell assays, also using recombinant cadherin ectodomain in comparison with collagen and vitronectin. Results Cadherin adherent cells adopt a fasciculated morphology, with a significant increase in neurite extension, measuring 104 ± 13.3 μm in length, compared with background adhesion on bovine serum albumin and nonfunctional cadherin ectodomain controls measuring 55 ± 4.4 and 47 ± 3.84 μm, respectively (p = 0.029). Significant increases in neurite length compared with controls were also observed in the vitronectin (81 ± 4.69 μm) and Type IV collagen (91 ± 7.7 μm) groups (p = 0.017 and 0.025, respectively). With respect to migration, U373 cells demonstrate increased invasion in response to cadherin ectodomain exposure, whereas vitronectin and Type IV collagen were not potent initiators of migration through the transwell barrier. Both adhesion and migration outcomes were noted in the absence of any relative changes in cell proliferation, indicating a primary role for the cadherin-based adhesion system in tumor invasion. Cadherin-based adhesion promotes increased adhesion, neurite outgrowth, and migration in human U373MG glioblastoma cells, providing a novel area of research for the development of therapeutic targets addressing local tumor invasion.

Are reported increases in incidence of primary CNS tumours real? An analysis of longitudinal trends in England, 1979–2003

Reported increases in the incidence of CNS tumours in the developed world in the 1970s to 1990s have been a cause for concern and debate. It still remains to be adequately answered whether these increases are true or an artefact of changes in diagnostic and registration practices. Using high-quality national cancer registration data, we have analysed incidence trends for each major histological subgroup of CNS tumour (2000 World Health Organisation (WHO) classification) registered in those aged 0–84 years for the whole of England during the period 1979 through 2003. 134,509 primary CNS tumours of malignant, benign and uncertain behaviour located in the brain, meninges, spinal cord, cranial nerves, other parts of the central nervous system and in the pituitary and pineal glands were registered. In summary, we present the single largest nationwide study on the longitudinal incidence trends of CNS tumours. The increase in incidence observed in the 1970s and 1980s was mainly in the young and the elderly and has now plateaued and may even be decreasing. There is however variation in trends by histology. The incidence of some histological sub-groups has continued to increase until the most recent period of analysis. Much of the initial increase can be attributed to the emergence of much more widely available neuroimaging, while the most recent incidence changes for specific sub-groups of CNS tumours appear to be due to greater diagnostic specificity leading to a shift in registered categories. However, the trends for high-grade astrocytomas and other gliomas need further observation and investigation.

Pre-clinical transgenic mouse models of nervous system tumors

AbstractThe most common primary CNS tumors are gliomas, where other than a few subtypes such as oligodendrogliomas, the survival has remained unchanged despite advances in surgical, chemo- and radiation therapy, especially for the most malignant and common glioma; glioblastoma multiforme (GBM). Recent novel therapies like immuno- and gene therapy have shown some promise in existing pre-clinical models, but have failed to demonstrate therapeutic benefit in patients. The reason(s) for such failures include our incomplete understanding of the molecular pathogenesis of these tumors and also due to testing of novel biological therapies in less than ideal pre-clinical models, which for the most part have included xenografts established in mice from glioma cell lines or patient explants. Transgenic mouse models offers an opportunity to develop and utilize an easily replenished, reproducible, manipulated spontaneous and more appropriate pre-clinical model of human cancers. Here we highlight on how mouse models are generated using several techniques and how mouse models have come to the forefront to address several issues such as identifying novel tumour modifier genes of central and peripheral nervous system tumours. Lastly we discuss how mouse models may provide an invaluable tool in pre clinical drug screening and testing.